1. Field of the Invention (Technical Field)
The present invention relates to coatings, methods of use of coating compositions, and coated contacting surfaces of medical devices, wherein the coating includes silyl-heparin with one or more bioactive molecules bound to the heparin, which bioactive molecules include adhesive molecules, such as fibronectin for promoting cellular attachment, growth factor molecules, such as basic fibroblast growth factor for promoting cellular growth, and a variety of other therapeutic molecules for effecting one or more therapeutic purposes.
2. Background Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Heparin is naturally present in various tissues, including liver and lung, as well as the luminal surface of endothelial cells. It is composed of repeating units of D-glucuronic acid and D-glucosamine, both sulfated, in a 1,4-α linkage. Heparin is an anticoagulant, and it has been reported that on the surface of endothelial cells it minimizes fibrin accumulation. When administered as a parenteral drug, heparin activates anti-thrombin III, which leads to inactivation of thrombin and ultimately systemic inhibition of fibrin formation.
A number of medical devices that come in contact with blood have been coated with heparin with the goal of taking advantage of its thrombo-resistant nature. Stents, catheters, oxygenator fibers, and cardiac bypass circuits are examples of medical devices that have been coated with heparin (Niimi et al., Anesth Analg 89:573-9, 1999; Inui et al., Artif Organs, 23:1107-12, 1999). Various strategies have been developed to attach heparin to medical polymer surfaces including chemical conjugation (Siefert et al., J Biomater Sci Polym Ed, 7:277-87, 1995), plasma glow discharge methods (Kim et al., Biomaterials, 21:121-30, 2000), the combination of both, and hydrophobic interaction as described herein (U.S. Pat. No. 5,955,588).
Heparin has a number of other biological actions related to its similarity to heparan sulfate. In the extracellular matrix, heparin and its chemical relative heparan sulfate is complexed into a scaffolding onto which cells attach. Heparin also binds to fibronectin and other adhesive molecules. In addition, extracellular matrix heparan sulfate and heparin also act as reservoirs for growth factors, not only binding growth factors but also protecting them from protease degradation. Fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and bone morphogenic protein (BMP) are examples of growth factors that complex to heparin.
The ability of heparin to bind adhesive molecules and growth factors has lead to a number of efforts to use heparin complexes to improve implantable medical device surfaces by providing surfaces to which cells can attach and migrate. Other researchers have explored direct coatings of fibronectin, and peptides and peptide mimetics derived from fibronectin, with the goal of increasing cell attachment (Walluscheck et al., Eur J Vasc Endovasc Surg, 12:321-30, 1996; Boxus et al., J Bioorg Med Chem, 6:1577-95, 1998; Tweden et al., J. Heart Valve Dis, 4 Suppl 1:S90-7, 1995). Vascular grafts, for example, would be improved by a surface that supports the growth of endothelial cells. Current vascular grafts of polytetrafluoroethylene and polyethylene terephthalate do not support endothelization, and consequently patients must be maintained on long-term ant-platelet therapy.
Fibronectins function as adhesive, ligand molecules interacting with specific receptors on the cell surface. Cells types that attach to fibronectin include fibroblasts, endothelial cells, smooth muscle cells, osteoblasts, and chondrocytes.
Other investigators have used heparin and fibronectin complexes to provide cell adhesion to polymeric surfaces. For example, heparin-albumin conjugates have been immobilized on carbon dioxide gas plasma-treated polystyrene (Bos et al., J. Biomed Mater Res, 47:279-91, 1999) and complexed to fibronectin. The fibronectin on these surfaces increased the attachment of endothelial cells. Bos et al. (Tissue Eng 4:267-79, 1998) reported that endothelial cells grew to confluency on CO2 gas plasma-treated polystyrene coated with an albumin-heparin conjugate. ishihara et al. (J Biomed Mater Res, 50: 144-152, 2000) reported that a heparin-conjugated polystyrene promoted cell attachment of fibroblasts, smooth muscle cell and endothelial cells. The fibroblasts grown on heparin-conjugated polystyrene had growth rates at least comparable to fibronectin-coated, gelatin-coated, or tissue culture-treated media.
A simple method of efficiently complexing fibronectin, other adhesive molecules, growth factor molecules, and therapeutic molecules, including derivatives or mimics of the foregoing, to a heparin complex would have wide applicability for attaching cells to prostheses, including vascular grafts, bone and cartilage Implants, nerve guides and the like. Particularly needed is a method and composition permitting use of a wide variety of adhesive molecules, including fibronectin, laminin and the like, and growth factor molecules, including FGF, as part of a coating for implantable medical devices.
There further remains a need in the art for coating compositions for implantable medical devices that promote cellular attachment, and further wherein cellular attachment can be modulated by the quantity of adhesive molecule, and which can be applied simply and easily with no specialized equipment or techniques.
A primary object of the present invention is to provide a coating composition for contacting surfaces of implantable medical devices, wherein the composition comprises a silyl-heparin-bioactive molecule complex, attached to the contacting surface by hydrophobic interaction.
A further object of the invention is to provide an amphipathic silyl-heparin-fibronectin coating composition for contacting surfaces of implantable medical devices, which promotes cellular attachment.
A further object of the invention is to provide a coating the composition of which can be varied, such that absent an adhesive molecule the coating inhibits fibrin deposition, but when the coating includes an adhesive molecule, the coating promotes cellular attachment and cell growth.
A further object of the invention is to provide a coating the composition of which can be varied, such that in one embodiment the invention provides a silyl-heparin-growth factor molecule composition, and in another embodiment the invention provides a silyl-heparin-therapeutic molecule composition.
A further object of the invention is to provide coating compositions utilizing fibronectin, derivations of fibronectin, peptide mimics of fibronectin, laminin, vitronectin, thrombospondin, gelatin, collagen and subtypes thereof, gelatin, polylysine, polyornithine, and other adhesive molecules or derivatives or mimics of other adhesive molecules.
A further object of the invention is to provide coating compositions utilizing fibroblast growth factor, platelet-derived growth factor, vascular endothelial growth factor, hepatocyte growth factor, placental growth factor, insulin-like growth factor, nerve growth factors and neurotrophins, heparin-binding epidermal growth factor, transforming growth factor-β, bone morphogenetic protein 2, osteogenic protein 1 and keratinocyte growth factor, and other growth factor molecules or derivatives or mimics of other growth factor molecules.
A further object of the present invention is to provide a cost effective and commercially feasible method for coating polymeric medical devices, including biodegradable medical devices, with a coating comprising a bioactive molecule.
A further object of the present invention is to provide a cost effective and commercially feasible method for coating polymeric medical devices, including biodegradable medical devices, with a coating comprising a silyl-heparin-bioactive molecule composition.
A primary advantage of the present invention is that it provides for coating contacting surfaces of medical devices of complex geometries and surfaces with a durable and low-cost coating that promotes the desired biological or therapeutic effect, depending on the bioactive molecule selected.
Another advantage of the present invention is that it provides a method for determining the disassociation rate of silyl-heparin-bioactive molecule complexes from contacting surfaces by, in part, determining the number or silyl units per silyl moiety, or the number of silyl moieties per heparin molecule, or both.
Other objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, taken in conjunction with the accompanying drawings, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.